Our goal for the competing renewal is to better understand how phenotypic covariation contributes to the genetic basis of skeletal fragility. Preliminary studies indicate that sets of adult traits are established during post-natal growth through functional interactions between matrix mineralization and bone surface expansions. Further, these functional relationships, which were consistent with current theories of how a strain-based biological feedback system operates, were deterministic of adult bone functionality and fragility. We hypothesize that phenotypic covariation is a genetically determined trait that simultaneously coordinates essential aspects of bone biology to match loading demands during development. We propose to test this hypothesis by mapping quantitative trait loci (QTLs) that alter phenotypic covariation (Aim 1) using C57BL/6J-ChrA/J Chromosome Substitution Strains (CSSs). Further, we hypothesize that allelic variants that alter phenotypic covariation result from an altered responsiveness to mechanical loading. We test this hypothesis by determining whether QTLs regulating phenotypic covariation and the adaptive response to exercise map to the same genomic regions (Aims 2, 3). Finding this association would mean that skeletal growth patterns could be used as a predictor of the responsiveness of bone to mechanical loading. Finally, we propose to systematically assess each level of structural hierarchy in order to assign biological functionality to the QTLs. To accomplish this, we combine QTL analyses with quantitative analyses of cellular activity and serum growth factors. Many CSSs will show alterations in a specific trait or a specific trait interaction, and this is expected to be associated with measurable changes in endocrine signals during growth. This genetic perturbation experiment thus allows us to seek a biological factor that acts as a common control coordinating cellular activities during growth (i.e., functional adaptation). We will focus on the GH/IGF axis since this is the primary determinant of post-natal growth. These studies will not only identify novel QTLs regulating trait interactions during growth, but the results should also provide important insight into how functional adaptation buffers the deleterious mechanical consequences of genetic variants leading to slender bone phenotypes. PUBLIC HEALTH RELEVANCE: Growing a robust, fracture-resistant skeleton is a major goal for many fracture risk reduction strategies. By using a systems approach relating genetic variants to patterns of skeletal growth and to mechanical function, we propose to gain a new understanding of how genetic variation in growth leads to "at-risk sets of adult traits" that increase fracture susceptibility.